Considerable progress has been made in the treatment of acute myeloid leukemia (AML). However, current therapeutic results are still unsatisfactory in untreated high-risk patients and poorer in those with primary refractory or relapsed disease. In older patients, reluctance by clinicians to treat unfit patients, higher AML cell resistance related to more frequent adverse karyotype and/or precedent myelodysplastic syndrome, and preferential involvement of chemorefractory early hemopoietic precursors in the pathogenesis of the disease further account for poor prognosis, with median survival lower than six months. A general agreement exists concerning the administration of aggressive salvage therapy in young adults followed by allogeneic stem cell transplantation; on the contrary, different therapeutic approaches varying in intensity, from conventional salvage chemotherapy based on intermediate–high-dose cytarabine to best supportive care, are currently considered in the relapsed, older AML patient population. Either patients’ characteristics or physicians’ attitudes count toward the process of clinical decision making. In addition, several new drugs with clinical activity described as “promising” in uncontrolled single-arm studies failed to improve long-term outcomes when tested in larger randomized clinical trials. Recently, new agents have been approved and are expected to consistently improve the clinical outcome for selected genomic subgroups, and research is in progress in other molecular settings. While relapsed AML remains a tremendous challenge to both patients and clinicians, knowledge of the molecular pathogenesis of the disease is fast in progress, potentially leading to personalized therapy in most patients.
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